Transmural gradients in ion channel and auxiliary subunit expression

Abstract

Evolution has acted to shape the action potential in different regions of the heart in order to produce a maximally stable and efficient pump. This has been achieved by creating regional differences in ion channel expression levels within the heart as well as differences between equivalent cardiac tissues in different species. These region- and species-dependent differences in channel expression are established by regulatory evolution, evolution of the regulatory mechanisms that control channel expression levels. Ion channel auxiliary subunits are obvious targets for regulatory evolution, in order to change channel expression levels and/or modify channel function. This review focuses on the transmural gradients of ion channel expression in the heart and the role that regulation of auxiliary subunit expression plays in generating and shaping these gradients.

Doctoral Dissertation

“… Several of the β‐subunits are promiscuous and may interact with more than one α‐subunit . Based on International Union of Basic and Clinical Pharmacology (IUPHAR) nomenclature …”

“…In human and canine hearts, there are marked differences in action potential morphology across the ventricular wall (Figure and Table ). Action potentials from the mid‐ and epicardial layers have a pronounced early repolarization resulting in a “spike‐and‐dome morphology” that is lacking in the endocardium.…”

“…I to,f predominates in the mid‐ and epicardium, whereas the slowly recovering I to,s dominates in the endocardium . I to,s has been ascribed to K V 1.4, but K V 1.5 may also contribute as K V 1.5 mRNA has consistently been found in human and canine ventricles and in many species the molecular identity of I to,s remains poorly defined . I to,f channels consist of a tetramer of pore‐forming K V 4 α subunits (Figure ) .…”

“…Currents recorded from heterologously expressed K V 4 channels do not recapitulate native cardiac I to,f and K V 4 subunits have been shown to assemble with several β subunits and other regulatory factors . The K + Channel Interaction Protein 2 (KChIP2) increases K V 4.3 current density by facilitating trafficking, slowing inactivation and accelerating recovery kinetics …”

Cellular mechanisms underlying the effects of cilostazol, milrinone, isoproterenol and ajmaline on electrographic and arrhythmic manifestations of early repolarization syndrome, and comparative analysis of the cardiac electrophysiological effects of the optical isomers of mexiletine

“…There is no doubt that depolarization abnormalities can contribute to development of J waves and related arrhythmogenesis [Meijborg 2016, Hoogendijk 2013, and several factors can modulate the transmural heterogeneity and the degree of both repolarization and depolarization abnormalities, including electrotonic coupling, "source-sink" relationship, transmural differences in tissue resistivity and transmural and regional distribution of other ion channels and gap junctions [Yan 1998, LeGrice 1995, Liu 1995, Nguyen 2012, Poelzing 2004, Yamada 2004, Gaborit 2007, Szentandrassy 2005, Rosati 2006, Soltysinska 2009, McKinnon 2016.…”